The localized drug delivery from a drug-eluting stent (DES) has been shown to be quite effective and accepted as one of the most promising treatment methods for preventing restenosis after stenting procedures. For example, a polymeric coating on a DES is designed to sustain appropriate drug release kinetics in order to deliver the therapeutic dose of the drug for the required time interval at the treatment site. An estimation of the real-time release rate is critical for characterization of the DES dosage forms.
With respect to testing drug elution properties of a DES, there are certain challenges to overcome. Most notably, when evaluating the sustained release of a candidate DES structure the test can consume significant time, spanning weeks or months for sustained release of these dosage forms. This is disadvantageous in early research, and therefore not conducive for efficient management of product development. An accelerated (short-term) in-vitro release method is helpful for achieving a more rapid assessment of the formulation and processing variables. Accelerated in-vitro drug release testing is also used as a quality control tool to (i) ensure the consistency of the product performance from batch-to-batch and (ii) assure the stability of the product during the established shelf life.
Characterization of in-vitro drug release profiles for drug products and medical devices with therapeutic agents is routinely accomplished using commercially available automated or semi-automated equipment fitted with specialized holders to accommodate a variety of drug products or devices. Chapter 724 in the US Pharmacopeia (USP) lists several suitable release apparatus designs with the most common applications for each type. The Apparatus 7 (Reciprocating Holder) variety has been used to characterize the release profile of the drug substance used on a coated stent, e.g., Everolimus, when submersed in a release media, e.g., porcine serum. Apparatus 7 utilizes a reciprocating sample holder to dip the drug eluting device in a vessel, e.g., a test tube, containing release media. There are, however, only a limited number of commercially available Apparatus 7 sample holder designs to accommodate a wide variety of drug/device configurations. As a result, companies often design and build custom sample holders to suit specific needs since commercially available choices have limited usefulness.
The most frequently used types of Apparatus 7 sample holder designs for holding a stent during dipping employ a pair of cylindrical or frustoconical bodies received over a mandrel. A pair of collets, at least one of which being capable of sliding along a carrying mandrel, engages each end of the stent. The arrangement secures a stent on the holder while the stent is dipped. FIGS. 1A and 1B illustrate in perspective examples of two such Apparatus 7-type reciprocating holders. Referring to FIG. 1A, the stent holder, shown supporting a stent 10, has two ends 3a, 3b received over a wire 5. Each end 3a, 3b has opposed conical faces 6a, 6b, or frustoconical bodies mated together at their respective frustums with a cylindrical portion 4 separating the frustums. The end 3a is movable along the mandrel 5 while the end 3b is fixed. End 3a has a collar 7. Referring to FIG. 1B, there is a second type of Apparatus 7-type reciprocating holder. It also has a pair of brackets 8a, 8b received over a mandrel. Each bracket has a frustoconical shape 9b arranged to face each other. Stent ends are placed against the conical surface. The sliding end 8a moves towards or away from the other end 8b according to the length of the stent.
The design types in FIGS. 1A and 1B do not, generally speaking, produce an optimal flow profile of release medium over drug-containing surfaces of a medical device during the drug release testing, especially in the case of a stent with both exterior and interior surfaces coated. This conclusion was reached based on, e.g., inconsistencies seen between measured in-vivo vs. in-vitro release properties for the same product. As a result, it was concluded that the known Apparatus 7-type holders tend to cause significant variability in the amount of drug released at each dipping time point, compromising the precision and accuracy of the test. The concern is most serious for stents drug coated on both interior and exterior surfaces.
Accordingly, there is a need to provide a stent or scaffold holder that reduces variability in a drug release profile measured during a real-time or an accelerated in-vitro drug release test of a medical device, such as a stent, where the variability is due to an undesirable flow profile over drug-eluting surfaces of the medical device caused by interfering surfaces of the medical device holder. An improved medical device holder should produce more accurate quality assurance from batch-to-batch of manufactured medical devices; provide better guidance during product development; and/or more accurate predictions of the in-vivo response (when an in vitro/in vivo correlation is established) when using an accelerated in-vitro drug release test method.